EDO-S101

EDO-S101 (Tinostamustine) is a fusion molecule comprising of the alkylator bendamustine and the HDAC-inhibitor vorinostat; displays potent activity in vitro in MM cell lines (IC50=1.6-4.8 uM) and ex vivo in cells isolated from MM patients; shows activity in CB17-SCID murine plasmacytoma model and in de novo Vk*MYC mice, also is the only drug with single-agent activity in the multidrug resistant Vk12653 murine model.Blood Cancer Phase 1 Clinical (In Vitro) :Tinostamustine inhibits HDAC activity in rat peripheral blood mononuclear cells (PBMCs) in a cellular assay by approximately 90% one hour after dosing with 10mg/kg i.v. HDAC inhibition in PBMCs could not be increased with higher doses up to 50mg/kg. Tinostamustine triggers apoptosis and shows strong antitumor activity in HL60 and Daudi cells. Initial in vitro experiments in HL60 cells shows an activation of the intrinsic pathway of apoptosis with cleavage of caspases 3, 9 and PARP and a marked reduction of anti-apoptotic proteins XIAP and Mcl-1. (In Vivo) :Intracellular HDAC inhibition of Tinostamustine, which occurs rapidly after dosing is at maximum activity already at the lowest dose of 10mg/kg and lasts for about 12-16 hours. Exposure to Tinostamustine causes a strong DNA repair response evidenced by activation of pH2AX and p53 in tumors taken from mice bearing subcutaneous human Burkitt’s lymphoma. Tumors of BL rapidly shrink or are completely eradicated after i.v.administration of Tinostamustine.